Through study of a cohort of 3 year survivors of childhood sarcoma, we have confirmed a rare familial cancer syndrome involving childhood sarcoma, breast cancer, and an array of other tumors in 6-7% of cases and demonstrated that it is most likely attributable to a rare autosomal dominant gene with high penetrance. We have demonstrated that, among survivors of childhood soft tissue sarcoma, gene carriers have a significantly increased risk of a second malignant neoplasm as compared with non gene carriers, and that the risk is increased by radiation in both groups. We now propose to extend the genetic epidemiologic family studies to include a cohort of 400 childhood bone sarcoma patients, (a) to determine the extent to which childhood bone sarcomas are involved in different familial cancer syndromes, (b) to define parameters for models that characterize these syndromes and which can be used for genetic counseling/linkage investigation, (c) to determine whether certain clinical- epidemiologic features discriminate between hereditary and non- hereditary cases and (d) to identify specific kindreds for collaborative investigation to localize gene(s) predisposing to cancer and to test for genetic heterogenity. The primary statistical tool that will be used to address these questions is segregation analysis under a generalized mixed model. A second primary objective will be to determine the risk of developing second tumors to the 400 childhood bone sarcoma patients. The study will consider the impact of heredity and cancer treatment (radiotherapy and chemotherapy) in explaining variation in risk to second tumors.